Published Online
on July 28, 2003

A more recent version of this article appeared on October 1, 2003

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Submitted on May 5, 2003
Revised on June 2, 2003

PPAR Inhibition of Cyclooxygenase-2, PGE₂ Synthase, and Inducible Nitric Oxide Synthase in Cardiac Myocytes

Mariela Mendez and Margot C. LaPointe^*

From the Hypertension and Vascular Research Division, Henry Ford Hospital, Detroit, Mich.

^* To whom correspondence should be addressed. E-mail: mclapointe{at}aol.com.

Abstract--Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear receptor superfamily. They regulate lipid metabolism, glucose homeostasis, cell proliferation, and differentiation and modulate inflammatory responses. We examined whether PPAR is functional in cultured neonatal ventricular myocytes and studied its role in inflammation. Western blots revealed PPAR in myocytes. When myocytes were transfected with a PPAR response element reporter plasmid (PPRE-TK-luciferase), the PPAR activator 15-deoxy-^12,14-prostaglandin J₂ (15dPGJ₂) increased promoter activity, whereas cotransfection of a dominant negative PPAR inhibited it. To determine the role of 15dPGJ₂ in expression of proinflammatory genes, we tested its effect on interleukin-1 induction of cyclooxygenase-2 (COX-2). 15dPGJ₂ decreased interleukin-1 stimulation of COX-2 by 40% and PGE₂ production by 73%. We next questioned whether 15dPGJ₂ was modulating the expression of inducible prostaglandin E₂ synthase (PGES) and found that it completely blocked interleukin-1 induction of PGES. Use of a second PPAR agonist, troglitazone, and the selective PPAR antagonist GW9662 demonstrated that the effects seen were PPAR-dependent. In addition, we found that 15dPGJ₂ blocked interleukin-1 stimulation of inducible nitric oxide synthase (iNOS). We concluded that 15dPGJ₂ may play an anti-inflammatory role in a PPAR-dependent manner, decreasing COX-2, PGES, and PGE₂ production, as well as iNOS expression.

Key words: myocytes • nitric oxide synthase • cyclooxygenase • prostaglandins

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